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Treatment Failures and Relapses in Onychomycosis: A Stubborn Clinical Problem

Treatment Failures and Relapses in Onychomycosis: A Stubborn Clinical Problem IntroductionOnychomycoses are common and frequently distressing conditions. They represent a spectrum of infectious disorders deserving prompt and appropriate care [1]. However, about 20–50% of patients do not respond to the potent antifungals [2, 3]. In addition, some patients who temporarily respond to treatment see their infection recur after a variable period of time. The rates of expected relapses in clinical practice are unclear and cannot be extrapolated from published trials. Indeed, they vary largely among studies and according to the commercial sponsors. In addition, these studies do not represent the day-to-day situation because they most often target a specific type of onychomycosis in relation with a selected type of fungus. The wide variety of onychomycoses is therefore not explored.Treatment failures and relapses occur even when rapid drug penetration is achieved into the nail and when fungicidal activity is suggested in vitro. Indeed, the efficacy of antifungals in onychomycoses may be several orders of magnitude lower in vivo than that predicted in selected in vitro testing. This evidence is clinically relevant, otherwise why should onychomycoses be treated for several consecutive months when using a purported fungicidal drug? Several factors described hereafter are involved in the therapeutic failures and relapses of these common superficial fungal infections.Diagnostic AccuracyMany general practitioners remain under the misconception that onychomycoses are easily diagnosed. However, accurate diagnosis may be problematic [1, 4], but it is imperative to reach in order to prevent ineffective and expensive therapy, disease relapse and drug-related risk exposure. Precision in the clinical diagnosis and the expertise with which material is sampled for laboratory purpose have a major influence upon the final diagnosis.Difficulties in diagnosing onychomycoses primarily result from the etiological diversity. A high proportion of onychmycoses are caused by dermatophytes, predominantly from the genus Trichophyton. However, nondermatophyte molds and yeasts can also be responsible for the disease. In Europe, dermatophytes may account for about 75%, and yeasts and molds for 10% each [1]. Diagnostic problems may be further caused by the presentation of mixed infections involving a combination of distinct pathogens [4, 5, 6]. Following a presumptive diagnosis of onychomycosis, mycological assessments designed to identify the causative pathogen(s) should be performed prior to treatment. The identification of the exact pathogens involved is crucial because some fungi, particularly in the groups of yeasts and nondermatophyte molds, are less sensitive or even unresponsive to certain antifungal drugs.Both microscopy and culture performed on adequate specimens are essential for diagnostic accuracy [4, 7]. The sensitivity of microscopy may be enhanced by the use of stains including blue Parker ink and several specific fluorochromes [8]. However, direct microscopy yields more than 10% false-negative data [4, 8]. In addition, discrepancies with culture occur in about one third of the cases, even with proper sampling and laboratory procedures [4]. This is in part due to the fact that fungi are modular organisms that can have visible but dead sections in direct microscopy. This leads to a KOH-positive, but culture-negative sample. Conversely, subungual scraping samples may yield a few viable arthroconidia all but overlooked in direct microscopy although growing at culture. In these instances, the issue is a KOH-negative, but culture-positive sample. The use of vital stains such as neutral red can help in distinguishing living from dead fungal cells under the microscope (fig. 1). This can only be performed on fresh smears from subungual hyperkeratosis and from scrapings of superficial white onychomycoses.Fig. 1Fungi in a nail scraping. Viable cells are stained by the neutral red vital stain.Histological sections of nail clippings notably increase the diagnostic accuracy because the invasiveness of the fungus can clearly be observed [5, 9, 10]. The location of the fungus can also be determined with precision (fig. 2). In some instances, this cannot be guessed by clinical inspection alone. The morphological aspect of the fungus can often distinguish dermatophytes from yeasts and molds (fig. 3). This can be used to prove the existence of a mixed infection involving more than one fungus [5, 9]. Two types of mixed infections can be observed according to the presence of the fungi at the same site or at different sites of the nail plate. In the first instance, one of the fungi may be a passive bystander or an opportunistic agent (fig. 3d). In the second eventuality, both fungi must be primary invaders and pathogens (fig. 4). Although additional diagnostic procedures, such as immunohistochemistry (fig. 5), flow cytometry and PCR analysis, are perhaps more accurate [9, 11]these methods are not generally available to the practicing clinician. From these samples, quantification of the fungal load can be performed using computer-assisted image analysis (fig. 6).Fig. 2Fungi in two distinct locations within the nail. T. mentagrophytes var. interdigitale (presumably the superficial infection) and T. violaceum (presumably the mid-part infection) grew at culture.Fig. 3Distinct morphological aspects of dermatophytes (a), Candida sp. (b), a nondermatophyte mold (c), and S. brevicaulis and a dermatophyte (d).Fig. 4Mixed fungal infection with two different aspects of hyphae in the superficial and deep portions of the nail.Fig. 5Immunohistochemical staining of fungi using an antibody directed to Aspergillus spp.Fig. 6False-color presentation for quantification of the fungal load using image analysis.Causative AgentsDermatophytes are the main pathogens for nails, especially the anthropophilic Trichophyton rubrum and Trichophyton mentagrophytes var. interdigitale [4, 12]. In regions of the world where endothrix tineacapitis due to Trichophyton tonsurans, Trichophyton violaceum or Trichophyton soudanense are prevalent, these fungi may also cause onychomycosis. These dermatophytes produce a mixture of keratinases and other proteases, and they can invade nails directly. The T. mentagrophytes complex, being more osmotolerant, can cause primary infection on the upper surface of the nail plate. The more hydrophilic T. rubrum usually invades from the moist and sheltered underside of the nail. Interestingly, T. soudanense and T. violaceum may invade the medial nail portion (fig. 2).The second most important group of pathogens is represented by Candida spp., mainly Candida albicans and Candida parapsilosis. These yeasts may attack nails mainly by causing paronychia and subungual inflammation, disrupting growth and turning the nail into a patchwork of sheltered hydrated pockets ideal for yeast growth. Subclinical alterations of the nail plate by detergents may facilitate this type of infection.Many incidental nondermatophyte molds can be harbored in clefts of onychodystrophies. This condition with positive culture deals with contaminants, and thus cannot be interpreted as onychomycosis. However, some nondermatophyte molds produce keratinases and may be able to establish themselves independently in the nail [5, 6, 11, 12, 13, 14, 15]. Indeed, in many nondermatophyte onychomycoses, no dermatophyte can be isolated despite repeated attempts [5, 16]. Other molds require dermatophyte synergism for colonization. In addition, some may be secondary colonizers, able to grow on nail material predigested by a dermatophyte, but unable to invade the intact nail independently. Thus, nondermatophyte molds causing onychomycosis fall into two main categories. The first group encompasses fungi that are nearly always isolated from nails as etiologic agents, such as Scytalidium dimidiatum and Scytalidium hyalinum. The second group is formed by opportunistic fungi that may be isolated as etiologic agents or contaminants, such as Scopulariopsis brevicaulis,Aspergillus sydowii and Onychocola canadensis.Some pathogen molds may exhibit their own unique disease pattern. Certain nondermatophytes like Acremonium spp. can invade the nail surface, while others like Scytalidium spp. are more often associated with distal-subungual onychomycosis. The exact pattern of infection of many opportunistic species remains unclear because of the confusion caused by the possible isolation of contaminants from culturally false-negative dermatophytosis specimens.Persistence and Relapse of OnychomycosisThe treatment of onychomycosis has undoubtedly improved over the last decade or so. The majority of patients can expect a complete and lasting cure following oral therapy. However, there is still a significant proportion of patients for whom persistent or relapsing disease is a problem despite the best efforts to eradicate the infection [1, 3]. The reasons for treatment failures and relapses are complex but often identifiable [1, 4, 17, 18].Onychomycosis relapse is defined as the reappearance of the same infection, whatever time has elapsed. It has been and continues to be a difficult and often insoluble issue of therapy for any type of fungal infections of the nail. This situation may correspond to recurrence or reinfection. Recurrence may be conveniently defined by the return of the disease within 1 year of therapy completion, implying that clinical signs were gone but mycological cure was not achieved with the initial treatment [18]. If a new onychomycosis episode occurs after 1 year, reinfection is more probable because it implies the previous infection was cured but there is a new infection. Thus, it is likely that the patient has an abnormal propensity for development of the disease. Indeed, it is acknowledged that relapse may be related to the patient’s lifestyle, genetic factors, occupation, clinical features of the initial infection, and even the climate in which patients live. Some patients may be also at particular risk for onychomycosis because they may have a yet undiagnosed silent infection. Alternatively, they may be in regular close contact with a reservoir of pathogenic fungi harbored by relatives or colleagues in some professional settings and sport activities. The elderly, diabetic patients and immunosuppressed individuals are at particular risk of developing long-standing onychomycosis [19]. It has also been suggested that some patients have a genetic susceptibility to developing onychomycosis.Clinical Indicators of Poor Treatment RespondersSeveral key clinical indicators are associated with increased risk for treatment failure. They include lateral nail infection, the yellow spike pattern and the involvement of over 25% total nail surface area. Fungal invasion usually spreads proximally against the stream of growth of the nail plate. Hence, a slower nail growth facilitates the persistence of the infection [20]. When the subungual keratinized portion is thickened, the accumulated horny material forms a fungal reservoir which is associated with a nearly growth-stunted nail dynamics.The occurrence of a dermatophytoma is also considered as a bad prognostic factor [21]. It corresponds to a highly concentrated and dense focus of fungi with thick shortened hyphae.The presence of resting conidia inside the nail plate represents a potent reservoir almost unaffected by antifungals [1]. Growth of hyphae and recurrence of onychomycosis may occur from these conidia when treatment is stopped. One way to circumvent this process consists of luring the dormant fungus by boosting its growth while on antifungal treatment [22, 23]. Both the BATT (boosted antifungal topical treatment) and BOAT (boosted oral antifungal treatment) methods are safe when the antifungal has a broad spectrum of activity and when the boosting period is limited to 1 week. As the natural host defenses are not impaired by the treatment, the risk of systemic spread of infection is not higher than in untreated patients with onychomycosis.Treatment ConsiderationsTreatment regimens need to take into consideration the nail sites favored by specific pathogens, as well as the drug susceptibilities and responses of the different fungi. A broad spectrum activity is important to eradicate dermatophytes as well as less common pathogens and opportunistic agents including yeasts and molds.There is no evidence to suggest that treatment failure is due to intrinsic fungal resistance. However, fungal conidia in their dormant state are more resistant than hyphae to the penetration and actions of antifungals [1]. Additionally, there is strain heterogeneity in drug response within even a single-pathogen infection [24]. The clinical experience shows that the fungicidal property as determined in selective in vitro assays does not help in curing mycologically proven onychomycosis within a couple of months of treatment. It is probable that a lack of consistent drug penetration may be responsible for some instances of treatment failure.In vitro data about susceptibility testing of fungal pathogens cannot be directly extrapolated to the in vivo situation. Indeed, many variables interfere with the determination of the minimal inhibitory concentration (MIC). The nature of the culture media, the inoculum size, the length and temperature of incubation and endpoints definition tremendously affect the data. In addition, testing is classically performed in conditions that support optimum growth of the test fungus. This contrasts with the in vivo situation where resting conidia may be abundant in infected nail. Thus, MIC values and the concept of fungicidal drug are not correlated with the clinical outcome, and thus may appear irrelevant when treating a patient with onychomycosis [1].The ex vivo corneofungimetry was designed to be more predictive of the clinical effectiveness [25, 26]. This bioassay showed that both itraconazole and terbinafine exhibited high antidermatophyte activity. Faster onset and longer post-therapy activity were demonstrated for itraconazole. The purported fungicidal property of terbinafine was not evidenced.ConclusionOnychomycosis is not a trivial and easy-to-treat disease. Improving the diagnostic accuracy is important. Several factors may interfere with the drug efficacy. In particular, in vitro data obtained in culture are not always predictive for the clinical efficacy. Factors of bad prognosis are the presence of dormant conidia which are less responsive to antifungals, sequestrated mycelium pockets and resistant fungal species. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Dermatology Karger

Treatment Failures and Relapses in Onychomycosis: A Stubborn Clinical Problem

Arrese, Jorge E.; Piérard, Gérald E.
Dermatology , Volume 207 (3): 6 – Jan 1, 2003
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Publisher
Karger
Copyright
© 2003 S. Karger AG, Basel
ISSN
1018-8665
eISSN
1421-9832
DOI
10.1159/000073086
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Abstract

IntroductionOnychomycoses are common and frequently distressing conditions. They represent a spectrum of infectious disorders deserving prompt and appropriate care [1]. However, about 20–50% of patients do not respond to the potent antifungals [2, 3]. In addition, some patients who temporarily respond to treatment see their infection recur after a variable period of time. The rates of expected relapses in clinical practice are unclear and cannot be extrapolated from published trials. Indeed, they vary largely among studies and according to the commercial sponsors. In addition, these studies do not represent the day-to-day situation because they most often target a specific type of onychomycosis in relation with a selected type of fungus. The wide variety of onychomycoses is therefore not explored.Treatment failures and relapses occur even when rapid drug penetration is achieved into the nail and when fungicidal activity is suggested in vitro. Indeed, the efficacy of antifungals in onychomycoses may be several orders of magnitude lower in vivo than that predicted in selected in vitro testing. This evidence is clinically relevant, otherwise why should onychomycoses be treated for several consecutive months when using a purported fungicidal drug? Several factors described hereafter are involved in the therapeutic failures and relapses of these common superficial fungal infections.Diagnostic AccuracyMany general practitioners remain under the misconception that onychomycoses are easily diagnosed. However, accurate diagnosis may be problematic [1, 4], but it is imperative to reach in order to prevent ineffective and expensive therapy, disease relapse and drug-related risk exposure. Precision in the clinical diagnosis and the expertise with which material is sampled for laboratory purpose have a major influence upon the final diagnosis.Difficulties in diagnosing onychomycoses primarily result from the etiological diversity. A high proportion of onychmycoses are caused by dermatophytes, predominantly from the genus Trichophyton. However, nondermatophyte molds and yeasts can also be responsible for the disease. In Europe, dermatophytes may account for about 75%, and yeasts and molds for 10% each [1]. Diagnostic problems may be further caused by the presentation of mixed infections involving a combination of distinct pathogens [4, 5, 6]. Following a presumptive diagnosis of onychomycosis, mycological assessments designed to identify the causative pathogen(s) should be performed prior to treatment. The identification of the exact pathogens involved is crucial because some fungi, particularly in the groups of yeasts and nondermatophyte molds, are less sensitive or even unresponsive to certain antifungal drugs.Both microscopy and culture performed on adequate specimens are essential for diagnostic accuracy [4, 7]. The sensitivity of microscopy may be enhanced by the use of stains including blue Parker ink and several specific fluorochromes [8]. However, direct microscopy yields more than 10% false-negative data [4, 8]. In addition, discrepancies with culture occur in about one third of the cases, even with proper sampling and laboratory procedures [4]. This is in part due to the fact that fungi are modular organisms that can have visible but dead sections in direct microscopy. This leads to a KOH-positive, but culture-negative sample. Conversely, subungual scraping samples may yield a few viable arthroconidia all but overlooked in direct microscopy although growing at culture. In these instances, the issue is a KOH-negative, but culture-positive sample. The use of vital stains such as neutral red can help in distinguishing living from dead fungal cells under the microscope (fig. 1). This can only be performed on fresh smears from subungual hyperkeratosis and from scrapings of superficial white onychomycoses.Fig. 1Fungi in a nail scraping. Viable cells are stained by the neutral red vital stain.Histological sections of nail clippings notably increase the diagnostic accuracy because the invasiveness of the fungus can clearly be observed [5, 9, 10]. The location of the fungus can also be determined with precision (fig. 2). In some instances, this cannot be guessed by clinical inspection alone. The morphological aspect of the fungus can often distinguish dermatophytes from yeasts and molds (fig. 3). This can be used to prove the existence of a mixed infection involving more than one fungus [5, 9]. Two types of mixed infections can be observed according to the presence of the fungi at the same site or at different sites of the nail plate. In the first instance, one of the fungi may be a passive bystander or an opportunistic agent (fig. 3d). In the second eventuality, both fungi must be primary invaders and pathogens (fig. 4). Although additional diagnostic procedures, such as immunohistochemistry (fig. 5), flow cytometry and PCR analysis, are perhaps more accurate [9, 11]these methods are not generally available to the practicing clinician. From these samples, quantification of the fungal load can be performed using computer-assisted image analysis (fig. 6).Fig. 2Fungi in two distinct locations within the nail. T. mentagrophytes var. interdigitale (presumably the superficial infection) and T. violaceum (presumably the mid-part infection) grew at culture.Fig. 3Distinct morphological aspects of dermatophytes (a), Candida sp. (b), a nondermatophyte mold (c), and S. brevicaulis and a dermatophyte (d).Fig. 4Mixed fungal infection with two different aspects of hyphae in the superficial and deep portions of the nail.Fig. 5Immunohistochemical staining of fungi using an antibody directed to Aspergillus spp.Fig. 6False-color presentation for quantification of the fungal load using image analysis.Causative AgentsDermatophytes are the main pathogens for nails, especially the anthropophilic Trichophyton rubrum and Trichophyton mentagrophytes var. interdigitale [4, 12]. In regions of the world where endothrix tineacapitis due to Trichophyton tonsurans, Trichophyton violaceum or Trichophyton soudanense are prevalent, these fungi may also cause onychomycosis. These dermatophytes produce a mixture of keratinases and other proteases, and they can invade nails directly. The T. mentagrophytes complex, being more osmotolerant, can cause primary infection on the upper surface of the nail plate. The more hydrophilic T. rubrum usually invades from the moist and sheltered underside of the nail. Interestingly, T. soudanense and T. violaceum may invade the medial nail portion (fig. 2).The second most important group of pathogens is represented by Candida spp., mainly Candida albicans and Candida parapsilosis. These yeasts may attack nails mainly by causing paronychia and subungual inflammation, disrupting growth and turning the nail into a patchwork of sheltered hydrated pockets ideal for yeast growth. Subclinical alterations of the nail plate by detergents may facilitate this type of infection.Many incidental nondermatophyte molds can be harbored in clefts of onychodystrophies. This condition with positive culture deals with contaminants, and thus cannot be interpreted as onychomycosis. However, some nondermatophyte molds produce keratinases and may be able to establish themselves independently in the nail [5, 6, 11, 12, 13, 14, 15]. Indeed, in many nondermatophyte onychomycoses, no dermatophyte can be isolated despite repeated attempts [5, 16]. Other molds require dermatophyte synergism for colonization. In addition, some may be secondary colonizers, able to grow on nail material predigested by a dermatophyte, but unable to invade the intact nail independently. Thus, nondermatophyte molds causing onychomycosis fall into two main categories. The first group encompasses fungi that are nearly always isolated from nails as etiologic agents, such as Scytalidium dimidiatum and Scytalidium hyalinum. The second group is formed by opportunistic fungi that may be isolated as etiologic agents or contaminants, such as Scopulariopsis brevicaulis,Aspergillus sydowii and Onychocola canadensis.Some pathogen molds may exhibit their own unique disease pattern. Certain nondermatophytes like Acremonium spp. can invade the nail surface, while others like Scytalidium spp. are more often associated with distal-subungual onychomycosis. The exact pattern of infection of many opportunistic species remains unclear because of the confusion caused by the possible isolation of contaminants from culturally false-negative dermatophytosis specimens.Persistence and Relapse of OnychomycosisThe treatment of onychomycosis has undoubtedly improved over the last decade or so. The majority of patients can expect a complete and lasting cure following oral therapy. However, there is still a significant proportion of patients for whom persistent or relapsing disease is a problem despite the best efforts to eradicate the infection [1, 3]. The reasons for treatment failures and relapses are complex but often identifiable [1, 4, 17, 18].Onychomycosis relapse is defined as the reappearance of the same infection, whatever time has elapsed. It has been and continues to be a difficult and often insoluble issue of therapy for any type of fungal infections of the nail. This situation may correspond to recurrence or reinfection. Recurrence may be conveniently defined by the return of the disease within 1 year of therapy completion, implying that clinical signs were gone but mycological cure was not achieved with the initial treatment [18]. If a new onychomycosis episode occurs after 1 year, reinfection is more probable because it implies the previous infection was cured but there is a new infection. Thus, it is likely that the patient has an abnormal propensity for development of the disease. Indeed, it is acknowledged that relapse may be related to the patient’s lifestyle, genetic factors, occupation, clinical features of the initial infection, and even the climate in which patients live. Some patients may be also at particular risk for onychomycosis because they may have a yet undiagnosed silent infection. Alternatively, they may be in regular close contact with a reservoir of pathogenic fungi harbored by relatives or colleagues in some professional settings and sport activities. The elderly, diabetic patients and immunosuppressed individuals are at particular risk of developing long-standing onychomycosis [19]. It has also been suggested that some patients have a genetic susceptibility to developing onychomycosis.Clinical Indicators of Poor Treatment RespondersSeveral key clinical indicators are associated with increased risk for treatment failure. They include lateral nail infection, the yellow spike pattern and the involvement of over 25% total nail surface area. Fungal invasion usually spreads proximally against the stream of growth of the nail plate. Hence, a slower nail growth facilitates the persistence of the infection [20]. When the subungual keratinized portion is thickened, the accumulated horny material forms a fungal reservoir which is associated with a nearly growth-stunted nail dynamics.The occurrence of a dermatophytoma is also considered as a bad prognostic factor [21]. It corresponds to a highly concentrated and dense focus of fungi with thick shortened hyphae.The presence of resting conidia inside the nail plate represents a potent reservoir almost unaffected by antifungals [1]. Growth of hyphae and recurrence of onychomycosis may occur from these conidia when treatment is stopped. One way to circumvent this process consists of luring the dormant fungus by boosting its growth while on antifungal treatment [22, 23]. Both the BATT (boosted antifungal topical treatment) and BOAT (boosted oral antifungal treatment) methods are safe when the antifungal has a broad spectrum of activity and when the boosting period is limited to 1 week. As the natural host defenses are not impaired by the treatment, the risk of systemic spread of infection is not higher than in untreated patients with onychomycosis.Treatment ConsiderationsTreatment regimens need to take into consideration the nail sites favored by specific pathogens, as well as the drug susceptibilities and responses of the different fungi. A broad spectrum activity is important to eradicate dermatophytes as well as less common pathogens and opportunistic agents including yeasts and molds.There is no evidence to suggest that treatment failure is due to intrinsic fungal resistance. However, fungal conidia in their dormant state are more resistant than hyphae to the penetration and actions of antifungals [1]. Additionally, there is strain heterogeneity in drug response within even a single-pathogen infection [24]. The clinical experience shows that the fungicidal property as determined in selective in vitro assays does not help in curing mycologically proven onychomycosis within a couple of months of treatment. It is probable that a lack of consistent drug penetration may be responsible for some instances of treatment failure.In vitro data about susceptibility testing of fungal pathogens cannot be directly extrapolated to the in vivo situation. Indeed, many variables interfere with the determination of the minimal inhibitory concentration (MIC). The nature of the culture media, the inoculum size, the length and temperature of incubation and endpoints definition tremendously affect the data. In addition, testing is classically performed in conditions that support optimum growth of the test fungus. This contrasts with the in vivo situation where resting conidia may be abundant in infected nail. Thus, MIC values and the concept of fungicidal drug are not correlated with the clinical outcome, and thus may appear irrelevant when treating a patient with onychomycosis [1].The ex vivo corneofungimetry was designed to be more predictive of the clinical effectiveness [25, 26]. This bioassay showed that both itraconazole and terbinafine exhibited high antidermatophyte activity. Faster onset and longer post-therapy activity were demonstrated for itraconazole. The purported fungicidal property of terbinafine was not evidenced.ConclusionOnychomycosis is not a trivial and easy-to-treat disease. Improving the diagnostic accuracy is important. Several factors may interfere with the drug efficacy. In particular, in vitro data obtained in culture are not always predictive for the clinical efficacy. Factors of bad prognosis are the presence of dormant conidia which are less responsive to antifungals, sequestrated mycelium pockets and resistant fungal species.

Journal

Dermatology – Karger

Published: Jan 1, 2003

Keywords: Antifungal; Onychomycosis; Conidia; Relapse; Corneofungimetry

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